Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. J Clin Endocrinol Metab 2006 Jan;91(1):79-84
Date
11/03/2005Pubmed ID
16263812DOI
10.1210/jc.2005-1882Scopus ID
2-s2.0-30344439815 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
CONTEXT: Medullary thyroid cancer (MTC) is a cancer of the parafollicular C cells that commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC.
OBJECTIVE: The objective of this study was to investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751.
RESULTS: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 d for irinotecan alone and more than 130 d for irinotecan plus CEP-751. Although irinotecan induced an S phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway.
CONCLUSIONS: Irinotecan treatment was highly effective in a preclinical model of human MTC, resulting in complete remission in 100% of the xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for the treatment of MTC.
Author List
Strock CJ, Park JI, Rosen DM, Ruggeri B, Denmeade SR, Ball DW, Nelkin BDAuthor
Jong-In Park PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Antineoplastic Agents, Phytogenic
Blotting, Western
Camptothecin
Carbazoles
Carcinoma, Medullary
Cell Cycle
Cell Division
Cell Line, Tumor
Checkpoint Kinase 1
Enzyme Inhibitors
Histones
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Protein Kinases
Protein-Tyrosine Kinases
S Phase
Signal Transduction
Thyroid Neoplasms
Transplantation, Heterologous
cdc25 Phosphatases